Caloric restriction (CR) is the well-studied dietary intervention to prolong longevity and retard aging in a wide range of species. Methionine restriction (MR) has also been shown to extend lifespan in rodents. In addition, we have shown that MR diet could increase mouse lifespan even if initiated at middle age. In contrast with the CR, the mechanisms how MR diets extend longevity and delay aging have been less explored. Despite some similarities between CR and MR effects, distinct features including increased food consumption in MR animals, different gene expression patterns and disparities in activation of cellular signaling pathways have been documented. These evidences have strongly supported the idea that MR diets might slow aging through routes that do not mimic those of CR. Our long-term objective is to identify the molecular mechanisms responsible for the increase in lifespan and health span of animals exposed to MR. Our grant proposal is designed to test the hypothesis that MR diet slows aging through increasing metabolic flexibility and insulin sensitivity, enhancing stress resistance signaling and modulating the somatotropic axis in mice. The research proposed will test a series of hypotheses about the mechanism of lifespan extension in MR mice. A comprehensive analysis a broad range of end points, from the assessment of molecular changes, functional parameters, metabolic homeostasis, stress pathways to very basic physiological alterations should have a high impact on the field of aging since the fundamental mechanisms underlying the beneficial effects of MR remain largely unknown. The outcomes of this proposal will provide the important mechanistic advances to our current understanding of the differential mechanisms of action of two of the most powerful models for lifespan extension in mammals.